The concept of the neurovascular unit is changing the way we investigate brain function and CNS disorders. The emphasis shifts from a purely neuronal focus towards an integrative view where cell-cell communication between all brain cells forms the basis for function and dysfunction. This new PPG seeks to dissect mechanisms of physiologic and pathologic coupling in the neurovascular unit, with a focus on interactions between vascular and neuronal compartments. In Project 1, we will assess matrix integrin signaling and trophic coupling between cerebral endothelial cells and neurons. We hypothesize that endothelium is a significant source of brain-derived neurotrophic factor (BDNF), so that loss of endothelial matrix integrity and vascular trophic support leads to neuronal dysfunction and death. In Project 2, we will test the hypothesis that sphingosine-1-phosphate (S1P) acts as an autocrine and paracrine mediator that stimulates both neuronal and vascular proliferation after brain injury, thus coupling together neurogenesis and angiogenesis. In Project 3, we will study the reverse vasoconstrictive hemodynamic coupling that occurs between intensely depolarized neurons and glia and the blood vessel. Differences in hemodynamic coupling in normal versus ischemic brain should reveal new pathways of brain dysfunction. All projects will be supported by a Neurovascular Coupling Core, where we will develop and apply novel optical imaging techniques to map neurovascular brain function in three dimensions over space and time. Synergy is built into close interactions between all projects. How do integrin signals in Project 1 affect S1P in Project 2, and conversely, can S1P modulate endothelial BDNF production? How does integrin, BDNF and S1P signaling defined in Projects 1 and 2 affect the reverse hemodynamic coupling measured in Projects 3? And can the optical imaging techniques provided by our Core be applied to the in vivo models of disrupted matrix and trophic coupling in Projects 1, 2 and 3? Finally, an Administrative Core will support admin and budget logistics, a computer database, and a neurovascular seminar series across all the departments represented in our program. This highly integrated PPG should enable us to dissect neurovascular coupling at many levels, including fast hemodynamic coupling at the tissue level, as well as slow matrix and trophic coupling at the cellular level. Brain activation paradigms are used to assess normal physiologic coupling, and disease models are used as "probes" to dissect pathologic coupling. These data will have significant impact not only on the understanding of brain function, but should also give us insight into how dysfunctional brain deteriorates in acute brain injury and neurodegeneration.